SAXS for Pharmaceuticals
Traditional pharmaceutical therapies are typically synthesized by chemical reaction and are undergoing a steady change to address more diverse disease pathways and hit more challenging targets. The result generates beyond the rule of five molecules, such as PROTACS, peptides and oligonucleotides, that present poor solubility or stability. These drug substances often require precise control of the material properties and complex formulation in order to deliver the dose reproducibly. Meanwhile, generics manufacturers face greater complexity when deformulating these products to produce lower cost alternatives.
Challenges
Brick dust or Grease ball
Many novel drug molecules have poor solubility, often as a consequence of favorable binding to new targets. As a material, these molecules tend to form strong crystal lattices and be ‘brick dust’ or be very lipophilic – the ’grease balls’. The approaches to formulation and their nanoscale structures to overcome these challenges, can vary significantly.
Stability of amorphous systems
Amorphous systems can overcome solubility challenges but often require a high fraction of polymer and comes at the price of stability due to their transient nature. Therefore, controlling the amorphous phase at optimum drug loading becomes a significant challenge.
Multimerization of oligos affecting manufacturing yield
Oligos are at the forefront of pharmaceutical research however they are prone to fold, cross-link and aggregate to form larger secondary structures, reducing their biological function. Mapping the process design space is often carried out to mitigate their formation, which may be subject to change during scale up.
Deformulation of complex products
Modern innovator drugs aren’t easily defined by their component parts, formulation types or the blend uniformity. Their functional behavior can often be found at the nanoscale where amorphous domains, lamellar spacing and lipid structures exist. Understanding what these are and how they evolve under changing conditions is often the key to their performance.
Solution
Small-Angle and Wide-Angle X-ray Scattering (SAXS/WAXS) provide direct, non-destructive insight into the phases and stability of amorphous solid dispersions, the structures of lipid-based drug delivery systems and oligomeric states under processing conditions to develop manufacturing design spaces. Using this information scientists can accelerate formulation and drug development programs or indeed the development of generics and biosimilars.
Information obtained
Particle Size & Distribution
Quantify particle size distributions and monitor aggregation in pharmaceutical formulations.
Internal Structure & Layering
Characterize internal architecture, layering, and nanostructure in drug carriers and formulations.
Crystallinity & Amorphous Structure
Measure crystallinity, polymorphism, and amorphous ordering to understand stability and performance.
Self-Assembly & Formulation Structure
Characterize lipid nanoparticles, nanoemulsions, polymer-based delivery systems, and solid dispersions.
Structural Stability & Transformation
Track structural changes during mixing, heating, freeze–thaw cycles, dissolution, and storage using in situ and time-resolved measurements.
Development & Quality Control
Apply non-destructive structural characterization across solid, semi-solid, and solution states from early formulation development through manufacturing and QC.
Data example
In this example, an oligomeric state of a protein is shown to form from the monomer and then convert to a fibril. Sometimes oligomers are the desired product, other times they can reduce yield in manufacturing or be precursor states to aggregation. In this case, the protein is α-synuclein and fibrillation is a known pathway for neurodegeneration in Parkinson’s disease. The SAXS data illustrated the transient nature of this intermediate step under biorelevant conditions giving insight to the mechanism of formation.
Figure 1. SAXS curves of fibrillating aSN followed over time (from blue to red).
Our solutions
